This NIEHS challenge grant is written in response to challenge topic 04-ES-102: Investigating gene x environment interaction using controlled human exposures. As stated in the RFA, "Carefully controlled exposures of human subjects to low levels of environmental toxicants, such as ambient particulate matter, ozone, or diesel exhaust, provide an opportunity to help augment animal studies and population-based studies to better understand the interaction of genetics and exposure (GxE). To address this topic, we will employ two approved exposure protocols to access response phenotypes of individuals to 0.4 ppm ozone for 2 hours, and inhalation of a 20,000 units of endotoxin. We will achieve this by recruiting volunteers into the ozone protocol, and then inviting those who complete the ozone study to undertake endotoxin challenge. Ozone is a commonly occurring pollutant, and endotoxin is a major component of particulate matter and bioaersols. The response phenotypes we will examine include lung function, airway inflammation, immunophenotyping of airway and circulating monocytes, macrophages and dendritic cells, airway and circulating phagocyte function (oxidative burst and phagocytosis of opsonized zymosan) and mediator secretion. Recruitment will initially be focused on the null and sufficient glutathione-S-transferase M1 (GSTM1) genotype and null vs. sufficient and single nucleotide polymorphisms (SNPs) for nicotinamide adenine dinucleotide (phosphate) reduced:quinone oxidoreductase (NQO1), with the resulting haplotypes. Other common single nucleotide polymorphisms (SNPs) of interest exist in NF-E2, related factor 2 (NRF2), GSTP1, GSTT1, glutathione peroxdiase (GPX1), Heme oxygenase-1 (HO-1), and Superoxidase dismutase 2 (SOD2), theCD14 gene promoter, TLR2, TLR4;IL-1 , IL-1R, and the TNF gene promoter. While recruitment is focused on GSTM1 and NQO1, allele frequencies of the other genes are high enough that assessment of the effect of these SNPs will be achieved as well. Gene expression profiling using mRNA recovered from airway and circulating cells will also be conducted to identify novel candidate genes that regulate response to ozone and LPS. PUBLIC HEALTH RELEVANCE: Knowledge obtained from this research can be used for mitigation of the effect of environmental pollutants on persons with lung and cardiovascular disease through development of personal mitigation strategies and policymaking. The Clean Air Act requires that the National Ambient Air Quality Standards protect vulnerable populations, including those which genetically define vulnerability. Finally, these studies will also add to fundamental advances in our understanding of the pathophysiology of common human conditions.